Design and Development of Novel Pyrazole-Thiadiazole Derivatives as NF-ĸB Inhibitor and Cardioprotective Effect against Isoproterenol Induced Myocardial Infarction in Sprague-Dawley Rats

Abstract

The present study was aimed to discover novel pyrazole-thiadiazole derivatives as potent NF-ĸB inhibitor and its cardioprotective effect against isoproterenol (ISO)-induced myocardial infarction (MI) in rats. The designed analogues showed potent inhibition of NF-κB transcriptional activity in luciferase assay. Among the tested derivatives, compound 6c revealed as a potent inhibitor of NF-κB. It has been found that 6c exerts protective effect via multiple mechanisms against MI, such as the levels of various cardiac injury biomarkers (creatine kinase, creatine kinase myocardial band, aminotransferase, alanine aminotransferase and lactate dehydrogenase) were found to be decreased after 6c administration as compared to ISO group. The effect of 6c was also investigated on oxidative stress via quantifying the level of various biomarkers (MDA, MPO, superoxide dismutase, and glutathione peroxidase-1). In histopathology analysis, 6c showed restoration of microstructural changes in cardiac tissues as compared to the ISO-treated group. The groups treated by 6c groups showed dose-dependent significant reduction of cell count in TUNEL analysis. In Western blot analysis, 6c causes significant modulation of Bcl2 family proteins and inhibition of phosphorylation of NF-κB and IκBα. It could be suggested that 6c exerts protective action against MI via modulation of apoptosis and oxidative stress, Bcl-2 genes, and NF-κB.